*Target (protein/gene name): bifunctional dihydrofolate reductase-thymidylate synthase

*Protein ID (NP or XP #) or Wolbachia#: TDR targetID: 3944

*Organism: Plasmodium falciparum

*Background/Disease Information: Plasmodium falciprum is commonly known to cause malaria in human. Malaria is
aused by a parasite that is passed from one human to another by the bite of infected Anopheles mosquitoes. After infection, the parasites (called sporozoites) travel through the bloodstream to the liver, where they mature and release another form, the merozoites. The parasites enter the bloodstream and infect red blood cells.

Essentiality of this protein: It is very essential since it avoids the usage of antibiotics and other medications.
(http://www.ncbi.nlm.nih.gov/pubmed/16549005)

Complex of enzymes: not significantly complex

*EC#: 1.5.1.3

Link to BRENDA EC# page:
http://www.brenda-enzymes.org/php/result_flat.php4?ecno=1.5.1.3&Suchword=&organism%5B%5D=Plasmodium+falciparum&show_tm=0

Enzyme Assay information (spectrophotometric, coupled assay ?, reagents):It is linked to sigma aldrich website. (http://www.sigmaaldrich.com/etc/medialib/docs/Sigma/Enzyme_Assay/dihydrofolatereductase.Par.0001.File.tmp/dihydrofolatereductase.pdf)
Structure Available (PDB or Homology model):
: http://www.pdb.org/pdb/explore/explore.do?structureId=1J3I

Target : see the link (http://tdrtargets.org/targets/view?gene_id=3944)

Current Inhibitors: listed below

INHIBITORS
ORGANISM
COMMENTARY
LITERATURE
IMAGE
(1E)-1-[4-[(3,5-dichloropyridin-4-yl)oxy]phenyl]ethanone thiosemicarbazone

-
[[@../literature/lit.php4?e=1.5.1.3&r=703329|703329]]

1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-benzylpyrazinediium)

minimal inhibitory concentration: 0.003536 mM
[[@../literature/lit.php4?e=1.5.1.3&r=711727|711727]]

1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-methylpyrazinediium)

minimal inhibitory concentration: 0.002418 mM
[[@../literature/lit.php4?e=1.5.1.3&r=711727|711727]]

1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-phenylpyrazinediium)

minimal inhibitory concentration: 0.018 mM
[[@../literature/lit.php4?e=1.5.1.3&r=711727|711727]]

1-(4-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine

-
[[@../literature/lit.php4?e=1.5.1.3&r=703329|703329]]

1-[3-(3,4-dichlorophenoxy)propyloxy]-5-isopropylbiguanide

i.e. PS-16
[[@../literature/lit.php4?e=1.5.1.3&r=703329|703329]]
-
1-[3-(4-chlorophenoxy)propyloxy]-5-isopropylbiguanide

i.e. PS-33
[[@../literature/lit.php4?e=1.5.1.3&r=703329|703329]]
-
2,2'-({6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}diimino)diethanol

minimal inhibitory concentration: 0.149 mM
[[@../literature/lit.php4?e=1.5.1.3&r=711727|711727]]

2,3-bis(hydrazino)quinoxaline

-
[[@../literature/lit.php4?e=1.5.1.3&r=703329|703329]]



Expression Information: upregulation ranking shows that this gene ranks in the mid 40-60% group of genes (In a form of early schizont and late trophozoite). Also, expression system is Escherichia coli bl21(de3).

Purification Method:

Image of protein (PyMol or etc):
1j3i_bio_r_500.jpg
P. falciparum dihydrofolate reductase-thymidylate synthase (DOI: 10.2210, UniProtKB: P13922).

http://www.pdb.org/pdb/explore/explore.do?structureId=1J3I
-Amino acid sequence:

*length of your protein in Amino Acids =

Molecular Weight of your protein in kiloDaltons using the Expasy ProtParamwebsite =

Orthologs: Numerous but first 10 are:
Arabidopsis thaliana NP_195183 THY-2 (thymidylate synthase 2); dihydrofolate reductase/ th... | OrthoMCL
Arabidopsis thaliana NP_179230 THY-1 (THYMIDYLATE SYNTHASE 1); dihydrofolate reductase/ th... | OrthoMCL
Babesia bovis 3I3R B Chain B, X-Ray Structure Dihydrofolate ReductaseTHYMIDYLA... | OrthoMCL
Babesia bovis XP_001609606.1 dihydrofolate reductase/thymidilate synthase ... | OrthoMCL
Brugia malayi Bm1_33465 thymidylate synthase, putative... | OrthoMCL
Caenorhabditis elegans Y110A7A.4 CE24124 WBGene00022455 thymidylate synthase status:Confirmed... | OrthoMCL
Cryptosporidium hominis Chro.40506 chain A, crystal structure of Dhfr ... | OrthoMCL
Cryptosporidium muris CMU_010300 thymidylate synthase family protein ... | OrthoMCL
Cryptosporidium neoformas XP_567501 thymidylate synthase ... | OrthoMCL
Cryptosporidium parvum cgd4_4460 dihydrofolate reductase-thymidylate synthase ... | OrthoMCL


- Druggability: druggability index: 1 (0 to 1 range)
- By orthology to known druggable target
=
Species
Known druggable target
Reference
Linked compounds
Homo sapiens
Thymidylate synthase
Show papers
show compounds
Plasmodium falciparum K1/Thailand
Dihydrofolate reductase
Show papers
show compounds
Mus musculus
Thymidylate synthase
Show papers
show compounds
Leishmania major
Dihydrofolate reductase
Show papers
show compounds
Plasmodium berghei strain ANKA
Dihydrofolate reductase
Show papers
show compounds
Toxoplasma gondii
Dihydrofolate reductase
Show papers
show compounds
Escherichia coli
Thymidylate synthase
Show papers
show compounds
Rattus norvegicus
Thymidylate synthase
Show papers
show compounds
Lactobacillus casei
Thymidylate synthase
Show papers
show compounds
Cryptosporidium hominis TU502
Dihydrofolate reductase
Show papers
show compounds
Filobasidiella neoformans
Thymidylate synthase
Show papers
show compounds
- By sequence similar to non ortholog
=
Species
Target
Length
Source
Identity
Alignment span
Reference
Linked compounds
Gallus gallus
Dihydrofolate reductase
189 aa
P00378
28.9%
201 aa
Show papers
show compounds
Rattus norvegicus
Dihydrofolate reductase
187 aa
NP_569084.1
29.8%
205 aa
Show papers
show compounds
Mus musculus
Dihydrofolate reductase
186 aa
P00375
30.7%
205 aa
Show papers
show compounds
Pneumocystis jirovecii
Dihydrofolate reductase
206 aa
Q9UUP5
32.7%
168 aa
Show papers
show compounds
Candida albicans
Dihydrofolate reductase
192 aa
P22906
30.2%
162 aa
Show papers
show compounds
Homo sapiens
Dihydrofolate reductase
186 aa
P00374
29.7%
202 aa
Show papers
show compounds
Pneumocystis carinii
Dihydrofolate reductase
206 aa
P16184
30.0%
170 aa
Show papers
show compounds
(website: http://tdrtargets.org/targets/view?gene_id=3944)

- Additional Info.: Ki: 0.03 nM, IC50: 1820.0 nM


(TDR info: http://tdrtargets.org/targets/view?gene_id=3944)